Measles (MV) causes disease worldwide despite efforts towards eradication by vaccine, largely because it is spread so readily between people. MV eradication is currently hindered by the endemic nature of MV in developing countries and the decreasing rate of vaccination in developed countries. MV disease is generally self-limited with several life-threatening complications due to the temporary immune suppression and to the central nervous system (CNS) invasion. CNS manifestations following MV infection may occur early after infection, in the case of acute encephalomyelitis. A second form of MV-induced CNS disease, progressive infectious encephalitis, known as measles inclusion body encephalitis (MIBE), occurs in immunosuppressed patients 1 to 6 months after measles infection. This is a lethal sequela that is common in the growing population of immunocompromised patients, who cannot receive or respond to MV vaccination. A third form of MV-induced neurological disease ? subacute sclerosing panencephalitis (SSPE) ? leads to fatal outcomes years after infection even in the presence of neutralizing antibodies. Data from recent US outbreaks show that the incidence of SSPE can be as high as 1 every 600 infected infants, highlighting the significance of this disease also for the immune competent population. There is no specific therapy for acute or persistent CNS manifestations of measles. We have applied the results of fundamental research to develop a new antiviral strategy for MV CNS infection, based on inhibiting membrane fusion during MV entry. A major impetus for this application is our finding that attachment of lipid moieties to a peptide (termed C-peptide) fusion inhibitor yields three major advantages: (1) increased potency; (2) ability to follow the virus to the site of fusion activation; and (3) CNS penetration. We have shown that our prototypical C-peptide prevents lethal encephalitis in a transgenic mouse model. We propose to assess the therapeutic efficacy of newly improved fusion inhibitory C-peptides. The strategy will be assessed in vitro, ex vivo, and in vivo using wild-type strain MV and CNS adapted strains in immune-compromised mice. The proposed work will address two Specific Aims: 1. To assess the antiviral efficacy of C-peptide fusion inhibitors: in vitro and ex vivo studies. 2. To evaluate therapeutic efficacy of C-peptide fusion inhibitors against MV infection in vivo and to provide the proof of concept for pre-clinical development.